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Cited by 126Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

Sex and age interact to determine clinicopathologic differences in Alzheimer’s disease

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Liesinger, Amanda M., Graff-Radford, Neill R., Duara, Ranjan, Carter, Rickey E., Hanna Al-Shaikh, Fadi S., Koga, Shunsuke, Hinkle, Kelly M., DiLello, Sarah K. +6 more·2018·Acta Neuropathologica
DOI 10.1007/s00401-018-1908-xPMC PMC6280837
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Abstract

Women reportedly make up two-thirds of Alzheimer's disease (AD) dementia sufferers. Many estimates regarding AD, however, are based on clinical series lacking autopsy confirmation. The Florida Autopsied Multi-Ethnic (FLAME) cohort was queried for AD cases with a total of 1625 identified ranging in age from 53 to 102 years at death. Standard neuropathologic procedures were employed and clinical information was retrospectively collected. Clinicopathologic and genetic data (MAPT and APOE) were stratified by sex. Within the neuropathologically diagnosed AD cohort, the overall number of women and men did not differ. Men were younger at onset of cognitive symptoms, had a shorter disease duration, and more often had atypical (non-amnestic) clinical presentations. The frequency of autopsy-confirmed AD among women and men stratified by age at death revealed an inverse U-shaped curve in men and a U-shaped curve in women, with both curves having inflections at approximately 70 years of age. Regional counts of neurofibrillary tangles differed in women and men, especially when examined by age intervals. Women had overall greater severity of neurofibrillary tangle counts compared to men, especially in the hippocampus. Men were more often classified as hippocampal sparing AD, whereas limbic predominant AD was more common in women. Men and women did not differ in frequency of MAPT haplotype or APOE genotype. Atypical clinical presentations, younger age at onset and shorter disease duration were more frequent in men, suggesting that the lower reported frequency of AD in men may be due to more frequent atypical clinical presentations not recognized as AD. Our data suggest that neuropathologically diagnosed AD cases have the same frequency of women and men, but their clinical presentations and ages at onset tend to differ.

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  • Women develop greater neurofibrillary degeneration, brain parenchymal loss, and cognitive decline.

    “Recent studies suggest that women develop greater neurofibrillary degeneration, brain parenchymal loss, and cognitive decline.52,53,54”

    From Sex differences in cognitive decline among US adults (2021) · cites this paper as [54]

    The Discussion (page unavailable) reports more severe hippocampal neurofibrillary tangles in women and cites neuroimaging findings of faster hippocampal atrophy. That supports a regional form of tissue loss, not greater brain-wide parenchymal loss. The Discussion and Results on clinical findings (pages unavailable) explicitly say that the rate of cognitive decline did not differ between women and men. (LLM, conf=0.91)

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  • Post mortem studies indicate that females have lower resistance to AD pathologies.

    “Moreover, post mortem studies indicate that females have lower resistance to AD pathologies. 70 , 71”

    From Unraveling sex differences in Alzheimer's disease and related endophenotypes with brain proteomes (2025) · cites this paper as [71]

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Research works printed but not linked: 28

  1. [1]Amador-Ortiz C Lin WL Ahmed Z Personett D Davies P Duara R TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer’s disease Ann Neurol 2007 61 435 445 10.1002/ana.21154 17469117 PMC2677204 · DOI · Paper page
  2. [2]Ardekani BA Convit A Bachman AH Analysis of the MIRIAD data shows sex differences in hippocampal atrophy progression J Alzheimers Dis 2016 50 847 857 10.3233/jad-150780 26836168 · DOI · Paper page
  3. [3]Bachman DL Wolf PA Linn RT Knoefel JE Cobb JL Belanger AJ Incidence of dementia and probable Alzheimer’s disease in a general population: the Framingham study Neurology 1993 43 515 10.1212/wnl.43.3_part_1.515 8450993 · DOI · Paper page
  4. [4]Barker WW Luis CA Kashuba A Luis M Harwood DG Loewenstein D Relative frequencies of Alzheimer disease, Lewy body, vascular and frontotemporal dementia, and hippocampal sclerosis in the state of Florida brain bank Alzheimer Dis Assoc Disord 2002 16 203 212 10.1097/00002093-200210000-00001 12468894 · DOI
  5. [5]Barnes LL Wilson RS Bienias JL Schneider JA Evans DA Bennett DA Sex differences in the clinical manifestations of Alzheimer disease pathology Arch Gen Psychiatry 2005 62 685 691 10.1001/archpsyc.62.6.685 15939846 · DOI · Paper page
  6. [7]Beach TG White CL Hamilton RL Duda JE Iwatsubo T Dickson DW Evaluation of alpha-synuclein immunohistochemical methods used by invited experts Acta Neuropathol 2008 116 277 288 10.1007/s00401-008-0409-8 18626651 PMC2708176 · DOI · Paper page
  7. [8]Berg L McKeel DW Miller JP Storandt M Rubin EH Morris JC Clinicopathologic studies in cognitively healthy aging and Alzheimer disease—relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype Arch Neurol 1998 55 326 335 10.1001/archneur.55.3.326 9520006 · DOI · Paper page
  8. [10]Chêne G Beiser A Au R Preis SR Wolf PA Dufouil C Gender and incidence of dementia in the Framingham heart study from mid-adult life Alzheimer’s Dementia 2015 11 310 320 10.1016/j.jalz.2013.10.005 PMC4092061 24418058 · DOI · Paper page
  9. [12]Craig MC Maki PM Murphy DG The women’s health initiative memory study: findings and implications for treatment Lancet Neurol 2005 4 190 194 10.1016/s1474-4422(05)01016-1 15721829 · DOI
  10. [14]Galton CJ Patterson K Xuereb JH Hodges JR Atypical and typical presentations of Alzheimer’s disease: a clinical, neuropsychological, neuroimaging and pathological study of 13 cases Brain 2000 123 Pt 3 484 498 10.1093/brain/123.3.484 10686172 · DOI
  11. [16]Jellinger KA Attems J Incidence of cerebrovascular lesions in Alzheimer’s disease: a postmortem study Acta Neuropathol 2003 105 14 17 10.1007/s00401-002-0634-5 12471455 · DOI
  12. [18]Koga S Ono M Sahara N Higuchi M Dickson DW Fluorescence and autoradiographic evaluation of tau PET ligand PBB3 to alpha-synuclein pathology Mov Disord 2017 32 884 892 10.1002/mds.27013 28440890 PMC5577807 · DOI
  13. [20]Launer LJ Andersen K Dewey ME Letenneur L Ott A Amaducci LA Rates and risk factors for dementia and Alzheimer’s disease: results from EURODEM pooled analyses. EURODEM incidence research group and work groups. European studies of Dementia Neurology 1999 52 78 84 10.1212/WNL.52.1.78 9921852 · DOI · Paper page
  14. [21]Maraganore DM Anderson DW Bower JH McDonnell SK Rocca WA Autopsy patterns for Parkinson’s disease and related disorders in Olmsted county, Minnesota Neurology 1999 53 1342 1344 10.1212/WNL.53.6.1342 10522897 · DOI
  15. [22]McKeith IG Boeve BF Dickson DW Halliday G Taylor JP Weintraub D Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB consortium Neurology 2017 89 88 100 10.1212/wnl.0000000000004058 28592453 PMC5496518 · DOI · Paper page
  16. [23]Mielke MM Vemuri P Rocca WA Clinical epidemiology of Alzheimer’s disease: assessing sex and gender differences Clin Epidemiol 2014 6 37 48 10.2147/clep.s37929 24470773 PMC3891487 · DOI · Paper page
  17. [25]Murray ME Lowe VJ Graff-Radford NR Liesinger AM Cannon A Przybelski SA Clinicopathologic and 11C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer’s disease spectrum Brain 2015 138 1370 1381 10.1093/brain/awv050 25805643 PMC4407190 · DOI · Paper page
  18. [26]Ossenkoppele R Schonhaut DR Scholl M Lockhart SN Ayakta N Baker SL Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer’s disease Brain 2016 139 1551 1567 10.1093/brain/aww027 26962052 PMC5006248 · DOI · Paper page
  19. [27]Petersen RC Roberts RO Knopman DS Geda YE Cha RH Pankratz VS Prevalence of mild cognitive impairment is higher in men. the mayo clinic study of aging Neurology 2010 75 889 897 10.1212/wnl.0b013e3181f11d85 20820000 PMC2938972 · DOI
  20. [28]Plassman BL Langa KM Fisher GG Heeringa SG Weir DR Ofstedal MB Prevalence of dementia in the United States: the aging, demographics, and memory study Neuroepidemiology 2007 29 125 132 10.1159/000109998 17975326 PMC2705925 · DOI · Paper page
  21. [31]Ruitenberg A Ott A van Swieten JC Hofman A Breteler MMB Incidence of dementia: does gender make a difference? Neurobiol Aging 2001 22 575 580 10.1016/S0197-4580(01)00231-7 11445258 · DOI · Paper page
  22. [32]Savva GM Wharton SB Ince PG Forster G Matthews FE Brayne C Age, neuropathology, and dementia N Engl J Med 2009 360 2302 2309 10.1056/nejmoa0806142 19474427 · DOI · Paper page
  23. [33]Smith CD Chebrolu H Wekstein DR Schmitt FA Markesbery WR Age and gender effects on human brain anatomy: a voxel-based morphometric study in healthy elderly Neurobiol Aging 2007 28 1075 1087 10.1016/j.neurobiolaging.2006.05.018 16774798 · DOI
  24. [34]Snowden JS Stopford CL Julien CL Thompson JC Davidson Y Gibbons L Cognitive phenotypes in Alzheimer’s disease and genetic risk Cortex 2007 43 835 845 10.1016/S0010-9452(08)70683-X 17941342 · DOI · Paper page
  25. [36]Thal DR Rub U Orantes M Braak H Phases of A beta-deposition in the human brain and its relevance for the development of AD Neurology 2002 58 1791 1800 10.1212/WNL.58.12.1791 12084879 · DOI · Paper page
  26. [37]Vina J Lloret A Why women have more Alzheimer’s disease than men: gender and mitochondrial toxicity of amyloid-beta peptide J Alzheimers Dis 2010 20 Suppl 2 S527 S533 10.3233/jad-2010-100501 20442496 · DOI · Paper page
  27. [38]Winblad B Amouyel P Andrieu S Ballard C Brayne C Brodaty H Defeating Alzheimer’s disease and other dementias: a priority for European science and society Lancet Neurol 2016 15 455 532 10.1016/s1474-4422(16)00062-4 26987701 · DOI · Paper page
  28. [39]Zhang YJ Xu YF Cook C Gendron TF Roettges P Link CD Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity Proc Natl Acad Sci USA 2009 106 7607 7612 10.1073/pnas.0900688106 19383787 PMC2671323 · DOI

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Authors
Liesinger, A. M., Graff-Radford, N. R., Duara, R., Carter, R. E., Hanna Al-Shaikh, F. S., Koga, S., Hinkle, K. M., DiLello, S. K., Johnson, M. F., Aziz, A., Ertekin-Taner, N., Ross, O. A., Dickson, D. W., & Murray, M. E.
Affiliations
  • Mayo Clinic in Florida (US)
  • Mount Sinai Medical Center (US)
Corresponding author
Murray, Melissa E.
ORCID
Venue
Acta Neuropathologica
Publisher
Springer Science and Business Media LLC
Published
2018-09-15
Volume
136
Issue
6
Pages
873-885
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
DOI
10.1007/s00401-018-1908-x
PMC
PMC6280837
OpenAlex
W2892051921
Cited by
126
References
11
Citations by year
2026: 14 · 2025: 31 · 2024: 14 · 2023: 19 · 2022: 10 · 2021: 16 · 2020: 8 · 2019: 13 · 2018: 1
FWCI
7.48
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Florida Department of Health (6AZ01, 8AZ06)
  • National Institute on Aging (R01 AG054449)
  • Gerstner Family Foundation (Career Development Award)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, sex differences, age at death, clinicopathological correlation, neurofibrillary tangles, atypical presentation, age of onset, disease duration, APOE genotype
MeSH terms
Age Factors, Aged, Aged, 80 and over, Aging, Alzheimer Disease, Autopsy, Brain, Female, Humans, Male, Middle Aged, Psychiatric Status Rating Scales, Sex Characteristics, Neurofibrillary Tangles, Statistics, Nonparametric

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